The Integrated Alzheimer's Disease Rating Scale (iADRS) Findings from the EXPEDITION3 Trial.

The Integrated Alzheimer's Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD dementia. A statistically significant difference between placebo and active drug was observed for iADRS score change from baseline at Week 28 (p=0.028) through Week 80 (p=0.015). Across the Phase 3 solanezumab trials, iADRS was the only tool that consistently differentiated between solanezumab and placebo groups. These findings suggest that the iADRS is a useful integrated measurement tool for treatment trials of individuals with mild AD dementia.

A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS).

It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer's disease (AD) are needed. The integrated Alzheimer's Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS - mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents.

Amyloid-ß-directed immunotherapy for Alzheimer's disease.

Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid-ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti-amyloid immunotherapy remains one of the most promising emerging strategies for developing disease-modifying treatments for AD. In this review, we examine the presently ongoing Aß-directed immunotherapies that have passed clinical development Phase IIa.

The influence of matrix type, diurnal rhythm and sample collection and processing on the measurement of plasma beta-amyloid isoforms using the INNO-BIA plasma Abeta forms multiplex assay.

OBJECTIVE: The aim of the study was to determine the extent to which plasma matrix types, diurnal rhythm and sample collection and processing procedures contribute to overall variability of measurements with the INNO-BIA plasma Abeta forms assay. METHODS: Plasma samples from healthy volunteers were collected at BARC-CRI. Analyte concentrations from various plasma matrix types (EDTA, heparin, fluoride) were compared to serum after collection of blood in commercial plastic and glass tubes. Sample processing variables including time and temperature before and after centrifugation, centrifugal force and plasma dilution factor were also investigated. Diurnal variability in plasma Abeta isoforms was determined in 29 healthy volunteers by analysis of EDTA plasma specimens serially collected over 24 hours and stored frozen following oral administration of a placebo treatment. All plasma samples from a given individual and experiment were analyzed in a single analytical run. RESULTS: Highest Abeta levels were obtained using EDTA-plasma samples (in contrast to serum, heparin, citrate, or fluoride). Addition of aprotinin to EDTA plasma had no effect on Abeta peptide recovery. The elapsed time and temperature exposure, before and after sample processing affects the recovery of Abeta isoforms. Analyte recovery was not significantly affected by the presence of platelets in plasma samples. At the subject level, analysis of serially collected EDTA plasma specimens from healthy volunteers revealed no evidence of diurnal variation in any of the Abeta isoforms investigated and results from samples collected on a monthly basis showed only very limited intra-individual variation. CONCLUSIONS: Optimal recovery of Abeta peptides was obtained from blood drawn into EDTA tubes and processed within 4 h. Plasma that was refrigerated after separation and analysed within 4 h gave comparable results to samples immediately processed and frozen at -70 degrees C.

Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease.

LY450139 dihydrate, a gamma-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 weeks. Treatment was well tolerated. Abeta(1-40) in plasma decreased by 38.2%; in CSF, Abeta(1-40) decreased by 4.42 +/- 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Abeta concentrations and a measurable decrease in CSF Abeta.

Risky decision making in Huntington's disease.

In the clinical setting, Huntington's disease is associated with problems in judgment and decision making, however, the extent of these problems and their association with clinical characteristics have not been assessed. Recently, a laboratory-based simulated gambling task has been used to quantify similar decision-making deficits in ventromedial frontal lobe damaged participants. We hypothesized that participants with Huntington's disease (HD) would show deficits on this gambling task. For this study, 14 HD participants were asked to make 100 selections from four decks of cards with varied payoffs in order to maximize winnings of play money. They were compared to 22 participants with Parkinson's disease (PD) and 33 healthy controls. After an initial period in which participants had to learn contingencies of the decks, the HD group made fewer advantageous selections than the PD and control groups. In HD, the number of advantageous selections in the gambling task was correlated with measures of memory and conceptualization but not disinhibition. Thus, people with HD may have had difficulties learning or remembering win/loss contingencies of the decks, or they may have failed to consistently take these into account in their card selections. These findings are consistent with current models of frontal-subcortical brain circuits and behavior.

Influence of Competing Distractors on Response Selection in Huntington's Disease and Parkinson's Disease.

Current theories of the basal ganglia suggest a functional role in filtering stimuli that are competing for response selection. We hypothesised that damage to the basal ganglia, as occurs in Huntington's disease (HD) and Parkinson's disease (PD), may alter the effects of distractors on this filtering process. Fourteen HD subjects, 16 PD subjects, and age-matched healthy controls performed an ignored repetition test of negative priming. Negative priming was defined as a significant time cost in responding to a target that shared features with the distractor from the previous trial. Results indicated that whereas healthy controls and PD subjects showed normal negative priming, HD subjects failed to show negative priming. The results indicate that disruption to cells in the neostriatum, but not necessarily to cells in the substantia nigra, may affect selective attention by altering the influence of distractor stimuli competing for action.

Patients' perception of stopping or continuing treatment of cervical dystonia with botulinum toxin type A.

Despite widespread commercial acceptance of botulinum toxin (BTX) for idiopathic cervical dystonia (ICD), no follow up has been performed to determine when and why some patients stop therapy. It has been suggested that some patients who stop BTX treatment may do so because of permanent improvement. We surveyed 155 patients with ICD who were treated over 6 years with BTX to determine when and why patients stopped treatment with BTX, and what adverse events and changes in dose and/or frequency of treatments occurred in those who continued treatment. Of the 133 (86.6%) individuals returning the surveys, 104 continued on BTX treatment and 29 had stopped therapy. Of the 29 subjects no longer receiving BTX, 11 individuals had only received one or two injections. Prior surgical treatment for ICD did not influence their decision to stop therapy. Of those 104 of 133 continuing on BTX treatments, two thirds of the subjects reported the injections always help, whereas one quarter estimated one set of injections did not help. One third of those continuing treatment reported the first injection was most helpful, whereas another one third felt all injections were similarly effective. After an initial adjustment, BTX dosages and frequency of treatment remained stable in this group.

PET imaging of the pre-synaptic dopamine uptake sites in rapid-onset dystonia-parkinsonism (RDP).

BACKGROUND: Rapid-onset dystonia-parkinsonism (RDP) is a genetic movement disorder characterized by abrupt onset over hours to days of bradykinesia, postural instability, dysphagia, dysarthria, and severe dystonic spasms with decreased levels of the dopamine metabolite, homovanillic acid (HVA), in cerebrospinal fluid (CSF). METHODS: We imaged the dopamine re-uptake system with [O-methyl-11C]beta-CFT ([11C]beta-CFT) in three severely affected individuals with RDP and four patients with idiopathic Parkinson's disease (IPD). Results were compared with those of age-matched normal volunteers. RESULTS: Positron emission tomography images from those patients with IPD demonstrated a dramatic reduction in the volume of distribution of [11C]beta-CFT whereas patients with RDP showed slightly elevated values. CONCLUSIONS: The data suggest that patients with RDP do not have a decrease in the number of dopamine re-uptake sites. Our findings suggest that, unlike the situation in IPD, low CSF HVA concentrations seen in RDP patients are not the result of degeneration of striatal dopamine terminals or loss of dopamine re-uptake sites.

Comparison of treatment of tardive dystonia and idiopathic cervical dystonia with botulinum toxin type A.

To compare clinical parameters of patients treated with botulinum toxin type A (BTX) for treatment of idiopathic cervical dystonia (ICD) and for tardive cervical dystonia (TCD), we studied 156 patients (149 with ICD and 7 with TCD) who were treated with serial injections of BTX over 5 years. We hypothesized that patients with TCD and ICD would demonstrate similar improvement in severity scores after treatment with BTX. The diagnosis, dates, dosages, and frequency of BTX injected and severity assessments were recorded into a computerized database. Nonparametric Wilcoxon rank sum and signed-rank tests were used to assess statistical significance. The change in severity scores between the first treatment and last treatment in both groups was not statistically significant (p = 0.4859), indicating similar improvement. The difference in BTX doses was significant (p = 0.0045). ICD patients (n = 149) received an average of 219.8 +/- 63.5 units and those with TCD (n = 7) were treated with an average dose of 287.4 +/- 60.3 units. The average number of days between treatments for individuals with ICD was 142.9 +/- 85.8, similar to that for persons with TCD (144.7 +/- 64.5) (p = 0.6075). Our analysis provides preliminary evidence that the improvement from the administration of BTX for patients with ICD and TCD is similar.

Anxiety and motor performance in Parkinson's disease.

Previous work has suggested that anxiety disorders are common in patients with Parkinson's disease. To study the relationship between anxiety and response fluctuations in Parkinson's patients further, we compared changes in Spielberger anxiety state scores with changes in parkinsonian disability as determined by the Parkinson's symptom diary (PSD). Anxiety state and PSD scores were obtained in 19 patients with idiopathic Parkinson's disease during on and off periods. Spielberger anxiety state scores were higher during off periods than during on periods (38.8 +/- 12.4 vs. 45.6 +/- 12.4, p < 0.03); further, the magnitude of the change in anxiety state scores was correlated with the change in PSD scores (rs = 0.616, p = 0.006). Spielberger anxiety trait scores were also correlated with disease duration. Our findings support existing data suggesting that anxiety can contribute significantly to morbidity in Parkinson's disease and suggest that anxiety varies with fluctuations in motor performance.

Distribution and uptake of glycine, glutamate and gamma-aminobutyric acid in the vagal nuclei and eight other regions of the rat medulla oblongata.

In order to study the central neurochemical control of the vagus nerve, the contents of glycine, GABA, glutamate and five other amino acids have been measured in ten anatomically distinct regions of the rat medulla oblongata. Additionally, the high affinity uptake of glycine, GABA, glutamate, and leucine were measured in the same ten medullary regions. The data support published evidence for glutamatergic and GABAergic transmission in the nucleus of the tractus solitarius (NTS), and glycinergic inhibition in the hypoglossal nucleus. The data also lead to the suggestion that GABA and glutamate may be taken up into glial cells which exist along fiber tracts.